Highlights of Cardiovascular Disease Prevention Studies Presented at the 2023 American Heart Association Scientific Sessions.

PURPOSE OF REVIEW: Focused review highlighting ten select studies presented at the 2023 American Heart Association (AHA) Scientific Sessions. RECENT FINDINGS: Included studies assessed semaglutide and cardiovascular outcomes in overweight or obese patients without diabetes (SELECT); dapagliflozin in patients with acute myocardial infarction without diabetes (DAPA-MI); effects of dietary sodium on systolic blood pressure in middle-aged individuals (CARDIA-SSBP); long-term blood pressure control after hypertensive pregnancy with physician guided self-management (POP-HT); effect and safety of zilebesiran, an RNA interference therapy, for sustained blood pressure reduction (KARDIA-1); recaticimab add-on therapy in patients with non-familial hypercholesterolemia and mixed hyperlipidemia (REMAIN-2); efficacy and safety of lepodisiran an extended duration short-interfering RNA targeting lipoprotein(a); safety and pharmacodynamic effects of an investigational DNA base editing medicine that inactivates the PCSK9 gene and lowers LDL cholesterol (VERVE-101); automated referral to centralized pharmacy services for evidence-based statin initiation in high-risk patients; and effects of intensive blood pressure lowering in reducing risk of cardiovascular events (ESPRIT). Research presented at the 2023 AHA Scientific Sessions emphasized innovative strategies in cardiovascular disease prevention and management.

Understanding repeat hospitalizations in intermediate-to-high risk aortic stenosis patients following transcatheter aortic valve replacement.

OBJECTIVES: We describe the causes, timing and predictors of readmissions and analyze its impact on clinical outcomes in intermediate-to-high-risk patients with severe symptomatic aortic stenosis (AS) who underwent transcatheter aortic valve replacement (TAVR). BACKGROUND: Intermediate-high risk TAVR patients with severe AS have an increased risk for hospital readmissions due to the high burden of comorbidities. METHODS: Patients who underwent TAVR from 2012 to 2018 at a single tertiary cardiac center were included and followed for 1 year. Readmissions were categorized as noncardiovascular (non-CV) and CV. RESULTS: A total of 611 patients (410 with no readmissions, 201 with ≥1 readmissions) were included. There was a total of 317 readmissions (mean: 1.58 ± 1.09 per readmitted patient) with 65 patients having ≥2 readmissions. 64.0% were non-CV and 36.0% were CV. The top three CV causes were pacemaker/implantable cardioverter-defibrillator placement, bleeding, and stroke. About 23% occurred at 1 m, the majority were CV; 45% occurred between 7 and 12 m, the majority were non-CV. Those with ≥1 readmissions had a higher burden of comorbidities including peripheral arterial disease, diabetes, immunosuppression, prior percutaneous coronary interventions, and dialysis. Readmissions were associated with higher 1-year mortality (adjusted hazard ratio: 2.53, 95% confidence interval: 1.40-4.59; p = 0.002). High-risk patients had higher non-CV readmissions (0.37 ± 0.79 vs. 0.25 ± 0.62; p = 0.044) compared to intermediate-risk patients but similar CV readmissions (p = 0.645). CONCLUSIONS: Understanding readmissions post-TAVR will promote the early identification of at-risk groups and the implementation of preventative measures to improve outcomes and reduce the burden and costs of readmissions.

A case report of an infiltrative cardiomyopathy in everyday practice: a specific cause that cannot be missed in the elderly.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a commonly misdiagnosed cardiac condition due to low disease awareness and perceived rarity, which frequently results in incorrect management and poor outcomes. Early and prompt diagnosis has become critical with emerging therapies that improve patient survival. CASE SUMMARY: A 68-year-old woman presented to a tertiary care centre with acute decompensated heart failure following recurrent hospitalizations for the same issue over the past several months. Transthoracic echocardiography revealed severe concentric left ventricular hypertrophy with grade III diastolic dysfunction. However, QRS voltage by 12-lead electrocardiogram (ECG) was discordant with the degree of left ventricular hypertrophy seen by echocardiography, and the patient had recurrent non-sustained ventricular tachycardia that necessitated implantable cardioverter-defibrillator implantation a few months prior. After aggressive diuresis, the patient completed cardiac magnetic resonance imaging that raised concern for cardiac amyloidosis. Subsequent serum and urine protein electrophoresis with associated immunofixation were within normal limits. Finally, ATTR-CM was confirmed by technetium-99m pyrophosphate scintigraphy with plans to initiate tafamidis after genetic testing. DISCUSSION: Patients >60 years of age with diastolic heart failure phenotypically similar to hypertrophic cardiomyopathy and/or hypertensive heart disease should always be evaluated for ATTR-CM. Features that increase suspicion include discordance between left ventricular wall thickness and ECG voltage, and signs/symptoms of a primary peripheral and autonomic neuropathy. Useful non-invasive diagnostic testing has also made the diagnosis of ATTR-CM inexpensive and possible without the need for an endomyocardial biopsy. Unfortunately, this patient's diagnosis of ATTR-CM came late in her disease course, which delayed the onset of definitive therapy.

Coexistent Hyperuricemia and Gout in Rheumatoid Arthritis: Associations With Comorbidities, Disease Activity, and Mortality.

OBJECTIVE: Although hyperuricemia and gout can complicate the course of rheumatoid arthritis (RA), the impact of these factors on outcomes in RA is unclear. We undertook this study to examine associations of coexistent hyperuricemia and gout with RA disease measures, RA treatments, and survival. METHODS: Participants from a longitudinal RA study were categorized by the presence of gout and serum urate (UA) status. Groups were compared by baseline patient characteristics, RA disease activity, treatments, and comorbidities. Associations of baseline serum UA levels with all-cause and cardiovascular disease (CVD)-related mortality were examined in multivariable survival analyses. RESULTS: Of 1,999 participants with RA, 341 (17%) had serum UA concentrations of >6.8 mg/dl, and 121 (6.1%) were diagnosed with gout. There were no significant associations of serum UA concentration or gout with RA disease activity or treatment at enrollment, with the exception that those with gout were more likely to be receiving sulfasalazine and less likely to be receiving nonsteroidal antiinflammatory drugs. After adjustments for age and sex, moderate hyperuricemia (serum UA >6.8 to ≤8 mg/dl) was associated with an increased risk of CVD-related mortality (hazard ratio 1.56 [95% confidence interval 1.11-2.21]). This association was attenuated and not significant following additional adjustment for comorbidities that more commonly accompany hyperuricemia. Results corresponding with serum UA concentrations of >8.0 mg/dl were similar, although not reaching statistical significance in any model. There were no associations of baseline serum UA concentration with all-cause mortality. CONCLUSION: Our study reports the frequency of hyperuricemia and gout in patients with RA. These results demonstrate strong associations of hyperuricemia with CVD mortality in this population, a risk that appears to be driven by excess comorbidity.

Novel Antioxidant Properties of Doxycycline.

Doxycycline (DOX), a derivative of tetracycline, is a broad-spectrum antibiotic that exhibits a number of therapeutic activities in addition to its antibacterial properties. For example, DOX has been used in the management of a number of diseases characterized by chronic inflammation. One potential mechanism by which DOX inhibits the progression of these diseases is by reducing oxidative stress, thereby inhibiting subsequent lipid peroxidation and inflammatory responses. Herein, we tested the hypothesis that DOX directly scavenges reactive oxygen species (ROS) and inhibits the formation of redox-mediated malondialdehyde-acetaldehyde (MAA) protein adducts. Using a cell-free system, we demonstrated that DOX scavenged reactive oxygen species (ROS) produced during the formation of MAA-adducts and inhibits the formation of MAA-protein adducts. To determine whether DOX scavenges specific ROS, we examined the ability of DOX to directly scavenge superoxide and hydrogen peroxide. Using electron paramagnetic resonance (EPR) spectroscopy, we found that DOX directly scavenged superoxide, but not hydrogen peroxide. Additionally, we found that DOX inhibits MAA-induced activation of Nrf2, a redox-sensitive transcription factor. Together, these findings demonstrate the under-recognized direct antioxidant property of DOX that may help to explain its therapeutic potential in the treatment of conditions characterized by chronic inflammation and increased oxidative stress.

Direct antioxidant properties of methotrexate: Inhibition of malondialdehyde-acetaldehyde-protein adduct formation and superoxide scavenging.

Methotrexate (MTX) is an immunosuppressant commonly used for the treatment of autoimmune diseases. Recent observations have shown that patients treated with MTX also exhibit a reduced risk for the development of cardiovascular disease (CVD). Although MTX reduces systemic inflammation and tissue damage, the mechanisms by which MTX exerts these beneficial effects are not entirely known. We have previously demonstrated that protein adducts formed by the interaction of malondialdehyde (MDA) and acetaldehyde (AA), known as MAA-protein adducts, are present in diseased tissues of individuals with rheumatoid arthritis (RA) or CVD. In previously reported studies, MAA-adducts were shown to be highly immunogenic, supporting the concept that MAA-adducts not only serve as markers of oxidative stress but may have a direct role in the pathogenesis of inflammatory diseases. Because MAA-adducts are commonly detected in diseased tissues and are proposed to mitigate disease progression in both RA and CVD, we tested the hypothesis that MTX inhibits the generation of MAA-protein adducts by scavenging reactive oxygen species. Using a cell free system, we found that MTX reduces MAA-adduct formation by approximately 6-fold, and scavenges free radicals produced during MAA-adduct formation. Further investigation revealed that MTX directly scavenges superoxide, but not hydrogen peroxide. Additionally, using the Nrf2/ARE luciferase reporter cell line, which responds to intracellular redox changes, we observed that MTX inhibits the activation of Nrf2 in cells treated with MDA and AA. These studies define previously unrecognized mechanisms by which MTX can reduce inflammation and subsequent tissue damage, namely, scavenging free radicals, reducing oxidative stress, and inhibiting MAA-adduct formation.

Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation.

OBJECTIVE: PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with alglucosidase-alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. CASE REPORT: At 2.5months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11months. However, 1month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. CONCLUSION: This report outlines the benefits of ERT with alglucosidase alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated.